Sialoglycan binding patterns of bacterial AB5 toxin B subunits correlate with host range and toxicity, indicating evolution independent of A subunits
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2022
Authors
Khan, N.
Sasmal, A.
Khedri, Z.
Secrest, P.
Verhagen, A.
Srivastava, S.
Varki, N.
Chen, X.
Yu, H.
Beddoe, T.
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Journal article
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Journal of Biological Chemistry, 2022; 298(5):101900-1-101900-14
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Naazneen Khan, Aniruddha Sasmal, Zahra Khedri, Patrick Secrest, Andrea Verhagen, Saurabh Srivastava, Nissi Varki, Xi Chen, Hai Yu, Travis Beddoe, Adrienne W. Paton, James C. Paton, and Ajit Varki
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Abstract
Many pathogenic bacteria secrete AB5 toxins that can act as virulence factors. Cytotoxic A subunits are delivered to the cytosol following B subunit binding to specific host cell surface glycans. Some B subunits are not associated with A subunits, e.g., YpeB of Yersinia pestis, the etiologic agent of plague. Plague has not been eradicated because of Y. pestis' adaptability to numerous hosts. We previously showed selective binding of other B5 pentamers to a sialoglycan microarray, with sialic acid (Sia) preferences corresponding to those prominently expressed by various hosts, e.g., N-acetylneuraminic acid (Neu5Ac; prominent in humans) or N-glycolylneuraminic acid (Neu5Gc; prominent in ruminant mammals and rodents). Here we report that A subunit phylogeny evolved independently of B subunits and suggest a future B subunit nomenclature based on bacterial species names. We also found via phylogenetic analysis of B subunits which bind Sias that homologous molecules show poor correlation with species phylogeny. These data indicate ongoing lateral gene transfers between species, including mixing of A and B subunits. Consistent with much broader host range of Y. pestis, we show that YpeB recognizes all mammalian Sia types, except for 4-O-acetylated ones. Notably, YpeB alone causes dose-dependent cytotoxicity, which is abolished by a mutation (Y77F) eliminating Sia recognition, suggesting that cell proliferation and death are promoted via lectin-like cross-linking of cell surface sialoglycoconjugates. These findings help explain the host range of Y. pestis and could be important for pathogenesis. Overall, our data indicate ongoing rapid evolution of both host Sias and pathogen toxin-binding properties.
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© 2022 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).